Loss of the cholinergic innervation to the adult rat hippocampal formation (HF) results in sympathohippocampal sprouting. In order to identify the targets of the septohippocampal (cholinergic) fibers, pilot studies have been completed using electron microscopic (EM) identification of horseradish peroxidase (HRP)-labeled terminals. Additional experiments employing acetylcholinesterase and HRP histochemistry at the EM level are proposed. Identification of sympathohippocampal terminals will be accomplished by EM analysis of degenerating profiles following superior cervical ganglionectomy and, if necessary, with EM autoradiography. The specificity of sprouting sympathetic axons for brain regions denervated of cholinergic fibers, and the results of experiments designed to characterize the stimulus initiating such sprouting, suggest that a specific tropic factor is involved. Recent studies indicate that a growth factor is present in the rat HF and can be assayed using a sensitive in vitro cell culture system developed by Dr. Frank Collins. Several experiments are proposed to characterize the temporal and regional specificity of this factor and its relationship to the in vivo sprouting of sympathetic fibers. Additional studies of regeneration sympathetic fibers will be performed to determine how long following a septal lesion the HF is receptive to growing sympathetic axons. Another major specificaim of the research proposed here is to study possible changes in putative neurotransmitter receptors using recently developed autoradiographic methods. Such experiments are appropriate due to the remarkable transmitter specificity of the sprouting response i.e., noradrenergic sprouting in response to cholinergic denervation. The extent to which putative receptors are altered is relevant to the question of "functional" replacement of one transmitter pathway for another. In that regard, all of the experiments outlined in this proposal are designed to uncover the mechanisms by which neuronal sprouting occurs and whether such rearrangements are functional and adaptive. Such knowledge is essential for understanding recovery of function following CNS injury, e.g., stroke and spinal cord injury.